HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
INVIRASE safely and effectively. See full prescribing information for
INVIRASE.
INVIRASE® (saquinavir mesylate) capsules and tablets, for oral use
Initial U.S. Approval: 1995
----------------------------RECENT MAJOR CHANGES-------------------------Warnings and Precautions (5)
12/2015
Risk of Serious Adverse Reactions Due to Drug Interactions (5.1)
03/2015 ---------------------------INDICATIONS AND USAGE---------------------------INVIRASE is an HIV-1 protease inhibitor indicated for the treatment of HIV1 infection in combination with ritonavir and other antiretroviral agents in
adults (over the age of 16 years). (1)
------------------------DOSAGE AND ADMINISTRATION---------------------•
INVIRASE must be administered in combination with ritonavir. (2)
•
Adults (over the age of 16 years ): INVIRASE 1000 mg twice daily (5 x
200 mg capsules or 2 x 500 mg tablets) in combination with ritonavir
100 mg twice daily. (2.1)
•
INVIRASE and ritonavir should be taken within 2 hours after a meal.
(2.1)
-------------------DOSAGE FORMS AND STRENGTHS-------------------200 mg capsules and 500 mg film-coated tablets (3)
------------------------------CONTRAINDICATIONS-----------------------------•
Patients with congenital or documented acquired QT prolongation,
patients with refractory hypokalemia or hypomagnesemia, or those on
concomitant therapy with other drugs that prolong the QT interval. (4)
•
INVIRASE is contraindicated in patients with complete atrioventricular
(AV) block without implanted pacemakers, or patients who are at high
risk of complete AV block. (4)
•
INVIRASE is contraindicated in patients with clinically significant
hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome)
to saquinavir, saquinavir mesylate, or any of its ingredients. (4)
•
INVIRASE when administered with ritonavir is contraindicated in
patients with severe hepatic impairment. (4)
•
Coadministration of INVIRASE/ritonavir with CYP3A substrates for
which increased plasma levels may result in serious or life-threatening
reactions. (4)
•
Coadministration of INVIRASE/ritonavir with rifampin due to the risk
of severe hepatotoxicity. (4)
------------------------WARNINGS AND PRECAUTIONS----------------------•
The concomitant use of INVIRASE/ritonavir and certain other drugs
may result in known or potentially significant drug interactions. Consult
the full prescribing information prior to and during treatment for
potential drug interactions. (5.1, 7.3)
•
•
•
•
•
QT and PR interval prolongations have been observed in a healthy
volunteer study. Use with caution in patients with preexisting
conduction system abnormalities and certain heart diseases. (5.2, 5.3,
12.2)
Patients on INVIRASE therapy may develop new onset or exacerbations
of diabetes mellitus (5.4), hyperglycemia (5.4), elevated cholesterol
and/or triglyceride concentrations (5.7), redistribution/accumulation of
body fat (5.9), and immune reconstitution syndrome (5.10). Monitor
cholesterol and triglycerides prior to therapy and periodically thereafter.
(5.7)
In patients with underlying hepatitis B or C, cirrhosis, chronic
alcoholism and/or other underlying liver abnormalities there have been
reports of worsening liver disease. (5.5)
Hemophilia: Spontaneous bleeding may occur and additional factor VII
may be required. (5.6)
Various degrees of cross-resistance have been observed. (5.11)
-------------------------------ADVERSE REACTIONS----------------------------The most common adverse reactions are nausea, vomiting, diarrhea, fatigue,
pneumonia, lipodystrophy and abdominal pain. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
1-800-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------------------DRUG INTERACTIONS-----------------------•
INVIRASE/ritonavir is a potent inhibitor of CYP3A, significantly
increasing the exposure of drugs primarily metabolized by CYP3A. (7.1)
•
Coadministration of INVIRASE/ritonavir with drugs that induce CYP3A
may result in decreased plasma concentrations of saquinavir and reduced
efficacy. (7.2)
•
Certain drugs or drug classes should not be coadministered with
INVIRASE/ritonavir based on drug interaction studies or predicted drug
interactions. (5.1, 7.2, 7.3)
------------------------USE IN SPECIFIC POPULATIONS-------------------•
Pregnancy: Use during pregnancy only if the potential benefit justifies
the potential risk to the fetus. (8.1)
•
Nursing Mothers: Do not breastfeed if HIV-1-infected mothers are
receiving INVIRASE therapy. (8.3)
•
Pediatric Use: Pediatric dose recommendations that are both reliably
effective and below thresholds of concern with respect to QT and PR
prolongation could not be determined (8.4)
•
Geriatric Use: Caution should be exercised due to greater frequency of
decreased hepatic, renal or cardiac function in elderly population. (8.5)
•
Impaired Renal Function: No initial dose adjustment is necessary for
patients with renal impairment. (8.6)
•
Impaired Hepatic Function: No dose adjustment is necessary for patients
with mild or moderate hepatic impairment. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2015
_______________________________________________________________________________________________________________________________________
1
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose 2.2 Administration for Patients Unable to Swallow Capsules 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions 5.2 PR Interval Prolongation 5.3 QT Interval Prolongation 5.4 Diabetes Mellitus / Hyperglycemia 5.5 Hepatotoxicity 5.6 Hemophilia 5.7 Hyperlipidemia 5.8 Lactose Intolerance 5.9 Fat Redistribution 5.10 Immune Reconstitution Syndrome 5.11 Resistance/Cross-resistance 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience in Adult Subjects 6.2 Clinical Trial Experience in Pediatric Subjects 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Potential for INVIRASE to Affect Other Drugs 8 10 11 12 13 14 16 17 7.2 Potential for Other Drugs to Affect INVIRASE 7.3 Established and Other Potentially Significant Drug Interactions 7.4 Drugs without Clinically Significant Interactions with
INVIRASE/ritonavir USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Impaired Renal Function 8.7 Impaired Hepatic Function OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES 14.1 Description of Clinical Studies in Adults HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION _______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION
Product identification in this document includes: INVIRASE in reference to saquinavir mesylate;
saquinavir 200 mg soft gel capsule formulation1 in reference to saquinavir active base.
1
INDICATIONS AND USAGE
INVIRASE in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV-1
infection in adults (over the age of 16 years).
The following points should be considered when initiating therapy with INVIRASE:
- The twice daily administration of INVIRASE in combination with ritonavir is supported by
safety data from the MaxCmin 1 trial [see Adverse Reactions (6.1)] and pharmacokinetic data
[see Clinical Pharmacology (12.3)].
- The efficacy of INVIRASE with ritonavir has not been compared against the efficacy of
antiretroviral regimens currently considered standard of care.
- The number of baseline primary protease inhibitor mutations affects the virologic response to
INVIRASE/ritonavir.
2
DOSAGE AND ADMINISTRATION
INVIRASE must be used in combination with ritonavir because ritonavir significantly inhibits
saquinavir’s metabolism to provide increased plasma saquinavir levels.
Cobicistat is not interchangeable with ritonavir to increase systemic exposure of saquinavir [see
Warnings and Precautions (5)].
2.1
Recommended Dose
• INVIRASE 1000-mg twice daily (5 x 200-mg capsules or 2 x 500-mg tablets) in combination with ritonavir
100-mg twice daily.
• Ritonavir should be taken at the same time as INVIRASE.
• INVIRASE and ritonavir should be taken within 2 hours after a meal.
1
The term “saquinavir soft gel capsules” used in this label refers to the drug product formerly marketed as “Fortovase” (saquinavir
200 mg soft gel capsule formulation). This formulation has been withdrawn from the market.
2
•
•
For patients already taking ritonavir 100-mg twice daily as part of their antiretroviral regimen, no additional
ritonavir is needed.
Pediatric dose recommendations that are both reliably effective and below thresholds of concern for QT and
PR interval prolongation could not be determined.
2.2
Administration for Patients Unable to Swallow Capsules
Open the INVIRASE capsules and place the contents into an empty container. Add 15 mL of either sugar syrup
or sorbitol syrup (for patients with Type 1 diabetes or glucose intolerance) OR 3 teaspoons of jam to the
contents of INVIRASE capsules that are in the container. Stir with a spoon for 30 to 60 seconds. Administer the
full amount prepared for each dose. Suspensions should be at room temperature before administering.
3
DOSAGE FORMS AND STRENGTHS
Capsules: 200 mg
Film-coated tablets: 500 mg
4
CONTRAINDICATIONS
QT interval prolongation and torsades de pointes have been reported rarely with INVIRASE/ritonavir use. Do
not use in patients with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia,
and in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval
[see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)].
INVIRASE is contraindicated in patients with complete atrioventricular (AV) block without implanted
pacemakers, or patients who are at high risk of complete AV block [see Warnings and Precautions (5.2)].
INVIRASE is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction,
Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients.
INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment.
Coadministration of INVIRASE/ritonavir is contraindicated with drugs that are CYP3A substrates for which
increased plasma levels may result in serious or life-threatening reactions. These drugs and potentially related
adverse events are listed in Table 1.
Table 1
Drug Class
Drugs That Are Contraindicated With INVIRASE/ritonavir
Drugs Within Class That Are
Clinical Comment
Contraindicated With
INVIRASE/ritonavir
Alpha 1adrenoreceptor
antagonist
Alfuzosin
Potentially increased alfuzosin concentrations can
result in hypotension.
Antiarrhythmics
Amiodarone, bepridil,
dofetilide, flecainide, lidocaine
(systemic), propafenone,
quinidine
Potential for serious and/or life-threatening cardiac
arrhythmia.
Antidepressant
Trazodone
Increased trazodone concentrations can result in
potentially life threatening cardiac arrhythmia.
Anti-infectives
Clarithromycin, erythromycin,
halofantrine, pentamidine
Potential for serious and/or life-threatening cardiac
arrhythmia.
3
Antimycobacterial
Agents
Rifampin
Rifampin should not be administered in patients
taking INVIRASE/ritonavir as part of an ART
regimen due to the risk of severe hepatocellular
toxicity.
Ergot Derivatives
Dihydroergotamine,
ergonovine, ergotamine,
methylergonovine
Potential for serious and life threatening reactions
such as ergot toxicity characterized by peripheral
vasospasm and ischemia of the extremities and
other tissues.
GI Motility Agent
Cisapride
Potential for serious and/or life threatening
reactions such as cardiac arrhythmias.
HIV-1 Protease
Inhibitor
Atazanavir
Potential for serious and/or life-threatening cardiac
arrhythmia.
HMG-CoA Reductase
Inhibitors
Lovastatin, Simvastatin
Potential for myopathy including rhabdomyolysis.
Immunosuppressant
Tacrolimus
Potential for serious and/or life-threatening cardiac
arrhythmia.
Neuroleptics
Pimozide
Chlorpromazine
Sertindole
Clozapine
Haloperidol
Mesoridazine
Phenothiazines
Thioridazine
Ziprasidone
Sildenafil (Revatio®)[for
treatment of pulmonary arterial
hypertension]
Potential for serious and/or life threatening
reactions such as cardiac arrhythmias.
Triazolam, orally administered
midazolam
Potential for serious and/or life threatening
reactions such as prolonged or increased sedation
or respiratory depression.
PDE5 Inhibitors
Sedative/Hypnotics
Increased potential for sildenafil-associated
adverse events (which include visual disturbances,
hypotension, prolonged erection, and syncope). A
safe and effective dose has not been established
when used with INVIRASE/ritonavir.
Triazolam and orally administered midazolam are
extensively metabolized by CYP3A4.
Coadministration of triazolam or orally
administered midazolam with INVIRASE/ritonavir
may cause large increases in the concentration of
these benzodiazepines.
Other drugs that are
CYP3A substrates
Dapsone
Disopyramide
Quinine
Potential for serious and/or life-threatening cardiac
arrhythmia.
4
5
WARNINGS AND PRECAUTIONS
INVIRASE must be used in combination with ritonavir. Please refer to the ritonavir full prescribing
information for additional precautionary measures.
INVIRASE is not recommended for use in combination with cobicistat. Dosing recommendations for this
combination have not been established. Cobicistat is also not recommended in combination with regimens
containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Please refer to the cobicistat
full prescribing information for additional precautionary measures.
If a serious or severe toxicity occurs during treatment with INVIRASE, INVIRASE should be interrupted until
the etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with fulldose INVIRASE may be considered. For antiretroviral agents used in combination with INVIRASE, physicians
should refer to the complete product information for these drugs for dose adjustment recommendations and for
information regarding drug-associated adverse reactions.
5.1
Risk of Serious Adverse Reactions Due to Drug Interactions
Initiation of INVIRASE/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A
or initiation of medications metabolized by CYP3A in patients already receiving INVIRASE/ritonavir, may
increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or
induce CYP3A may increase or decrease concentrations of INVIRASE/ritonavir, respectively. These
interactions may lead to:
•
•
•
Clinically significant adverse reactions potentially leading to severe, life threatening, or fatal events
from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of INVIRASE/ritonavir.
Loss of therapeutic effect of INVIRASE/ritonavir and possible development of resistance.
See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including
dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and
during INVIRASE/ritonavir therapy; review concomitant medications during INVIRASE/ritonavir therapy; and
monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and
Drug Interactions (7)].
5.2
PR Interval Prolongation
Saquinavir/ritonavir prolongs the PR interval in a dose-dependent fashion. Cases of second or third degree
atrioventricular block have been reported rarely. Patients with underlying structural heart disease, pre-existing
conduction system abnormalities, cardiomyopathies and ischemic heart disease may be at increased risk for
developing cardiac conduction abnormalities. ECG monitoring is recommended in these patients [see Warnings
and Precautions (5.3)].
The impact on the PR interval of co-administration of saquinavir/ritonavir with other drugs that prolong the PR
interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been
evaluated. As a result, co-administration of saquinavir/ritonavir with these drugs should be undertaken with
caution, particularly with those drugs metabolized by CYP3A, and clinical monitoring is recommended [see
Clinical Pharmacology (12.2)].
5.3
QT Interval Prolongation
Saquinavir/ritonavir causes dose-dependent QT prolongation. Torsades de pointes has been reported rarely postmarketing. Avoid saquinavir/ritonavir in patients with long QT syndrome. ECG monitoring is recommended if
therapy is initiated in patients with congestive heart failure, bradyarrhythmias, hepatic impairment and
electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating saquinavir/ritonavir and
monitor these electrolytes periodically during therapy. Do not use in combination with drugs that both increase
5
saquinavir plasma concentrations and prolong the QT interval (see Tables 1 and 3) [see Clinical Pharmacology
(12.2)].
Patients initiating therapy with INVIRASE/ritonavir:
An ECG should be performed prior to initiation of treatment. Patients with a QT interval > 450 msec should
not receive ritonavir-boosted INVIRASE. For patients with a QT interval < 450 msec, an on-treatment ECG is
suggested after approximately 3 to 4 days of therapy; patients with a QT interval > 480 msec or prolongation
over pre-treatment by > 20 msec should discontinue INVIRASE/ritonavir.
Patients requiring treatment with medications with the potential to increase the QT interval and concomitant
INVIRASE/ritonavir:
Such combinations should only be used where no alternative therapy is available and the potential benefits
outweigh the potential risks. An ECG should be performed prior to initiation of the concomitant therapy, and
patients with a QT interval > 450 msec should not initiate the concomitant therapy. If baseline QT interval <
450 msec, an on-treatment ECG should be performed after 3-4 days of therapy. For patients demonstrating a
subsequent increase in QT interval to > 480 msec or increase by > 20 msec after commencing concomitant
therapy, the physician should use best clinical judgment to discontinue either INVIRASE/ritonavir or the
concomitant therapy or both.
A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of
ECG assessment.
5.4
Diabetes Mellitus / Hyperglycemia
New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been
reported during postmarketing surveillance in HIV-1-infected patients receiving protease-inhibitor therapy.
Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for the
treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued
protease-inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported
voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between
protease-inhibitor therapy and these events has not been established.
5.5
Hepatotoxicity
In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver
abnormalities, there have been reports of worsening liver disease.
5.6
Hemophilia
There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease
inhibitors. In some patients additional factor VIII was required. In the majority of reported cases treatment with
protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and
these episodes has not been established.
5.7
Hyperlipidemia
Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in
combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of
pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing
regimen of INVIRASE with ritonavir, and at periodic intervals while on such therapy. In these patients, lipid
disorders should be managed as clinically appropriate.
5.8
Lactose Intolerance
Each capsule contains lactose (anhydrous) 63.3 mg. This quantity should not induce specific symptoms of
intolerance.
6
5.9
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo
hump), facial wasting, peripheral wasting, breast enlargement, and “cushingoid appearance” have been
observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these
events are currently unknown. A causal relationship has not been established.
5.10
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy,
including INVIRASE. During the initial phase of combination antiretroviral treatment, patients whose immune
system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis),
which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been
reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can
occur many months after initiation of treatment.
5.11
Resistance/Cross-resistance
Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. Continued
administration of INVIRASE therapy following loss of viral suppression may increase the likelihood of cross
resistance to other protease inhibitors [see Microbiology (12.4)].
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
•
•
PR Interval Prolongation [see Warnings and Precautions (5.2)]
QT Interval Prolongation [see Warnings and Precautions (5.3)]
6.1
Clinical Trial Experience in Adult Subjects
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in clinical practice.
The original INVIRASE safety database consisted of a total of 574 adult subjects who received saquinavir 600
mg alone or in combination with ZDV or ddC. Combination dosing with ritonavir is based on 352 HIV-1
infected subjects and 166 healthy subjects who received various combinations of either saquinavir (hard gel or
soft-gel capsules) with ritonavir.
The recommended dose of INVIRASE is 1000 mg twice daily co-administered with ritonavir 100 mg twice
daily, in combination with other antiretroviral agents. Table 2 lists grade 2, 3 and 4 adverse events that occurred
in ≥2% of subjects receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).
Grade 2, 3 and 4 Adverse Events (All Causalitya) Reported in ≥2% of Adult Subjects in
the MaxCmin 1 Study of Saquinavir Soft Gel Capsules in Combination with Ritonavir
1000/100 mg twice a day
Adverse Events
Saquinavir soft gel capsules 1000 mg plus
Ritonavir 100 mg bid (48 weeks)
N=148
n (%=n/N)
Endocrine Disorders
Diabetes mellitus/hyperglycemia
4 (3)
Lipodystrophy
8 (5)
Gastrointestinal Disorders
Nausea
16 (11)
Table 2
7
a
Vomiting
Diarrhea
Abdominal Pain
Constipation
General Disorders and Administration Site Conditions
Fatigue
Fever
Musculoskeletal Disorders
Back Pain
Respiratory Disorders
Pneumonia
Bronchitis
Influenza
Sinusitis
Dermatological Disorders
Rash
Pruritus
Dry lips/skin
Eczema
11 (7)
12 (8)
9 (6)
3 (2)
9 (6)
5 (3)
3 (2)
8 (5)
4 (3)
4 (3)
4 (3)
5 (3)
5 (3)
3 (2)
3 (2)
Includes events with unknown relationship to study drug
Limited experience is available from three trials investigating the pharmacokinetics of the INVIRASE 500 mg
film-coated tablet compared to the INVIRASE 200 mg capsule in healthy volunteers (n=140). In two of these
trials saquinavir was combined with ritonavir; in the other trial, saquinavir was administered as single drug. The
INVIRASE tablet and the capsule formulations were similarly tolerated. The most common adverse events were
gastrointestinal disorders (such as nausea, vomiting, and diarrhea). Similar bioavailability was demonstrated
and no clinically significant differences in saquinavir exposures were seen. Thus, similar safety profiles are
expected between the two INVIRASE formulations.
A study investigating the drug-drug interaction of rifampin 600 mg/day daily and INVIRASE 1000 mg/ritonavir
100 mg twice daily enrolled 28 healthy volunteers. Eleven of 17 healthy volunteers (65%) exposed
concomitantly to rifampin and INVIRASE/ritonavir developed severe hepatocellular toxicity which presented
as increased hepatic transaminases. In some subjects, transaminases increased up to >20-fold the upper limit of
normal and were associated with gastrointestinal symptoms, including abdominal pain, gastritis, nausea, and
vomiting. Following discontinuation of all three drugs, clinical symptoms abated and the increased hepatic
transaminases normalized [see Contraindications (4)].
Additional Adverse Reactions Reported During Clinical Trials with Saquinavir
Blood and lymphatic system disorders: anemia, hemolytic anemia, leukopenia, lymphadenopathy,
neutropenia, pancytopenia, thrombocytopenia
Cardiac disorders: heart murmur, syncope
Ear and labyrinth disorders: tinnitus
Eye disorders: visual impairment
Gastrointestinal disorders: abdominal discomfort, ascites, dyspepsia, dysphagia, eructation, flatulence,
gastritis, gastrointestinal hemorrhage, intestinal obstruction, mouth dry, mucosal ulceration, pancreatitis
General disorders and administration site conditions: anorexia, asthenia, chest pain, edema, lethargy,
wasting syndrome, weight increased
8
Hepatobiliary disorders: chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, portal
hypertension
Immune system disorders: allergic reaction
Investigations: ALT increase, AST increase, blood creatine phosphokinase increased, increased alkaline
phosphatase, GGT increase, raised amylase, raised LDH
Metabolism and nutrition disorders: increased or decreased appetite, dehydration, hypertriglyceridemia
Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms, myalgia, polyarthritis
Neoplasms benign, malignant and unspecified (incl cysts and polyps): acute myeloid leukemia,
papillomatosis
Nervous system disorders: confusion, convulsions, coordination abnormal, dizziness, dysgeusia, headache,
hypoaesthesia, intracranial hemorrhage leading to death, loss of consciousness, paresthesia, peripheral
neuropathy, somnolence, tremor
Psychiatric disorders: anxiety, depression, insomnia, libido disorder, psychotic disorder, sleep disorder,
suicide attempt
Renal and urinary disorders: nephrolithiasis
Respiratory, thoracic and mediastinal disorders: cough, dyspnea
Skin and subcutaneous tissue disorders: acne, alopecia, dermatitis bullous, drug eruption, erythema, severe
cutaneous reaction associated with increased liver function tests, Stevens-Johnson syndrome, sweating
increased, urticaria
Vascular disorders: hypertension, hypotension, thrombophlebitis, peripheral vasoconstriction
6.2
Clinical Trial Experience in Pediatric Subjects
Limited safety data are available from two pediatric clinical trials of saquinavir hard gel capsules
(approximately 50 mg per kg twice daily) used in combination with either low dose ritonavir or
lopinavir/ritonavir. These trials enrolled pediatric subjects aged 4 months to 16 years old. In the HIVNAT 017
study (INVIRASE + lopinavir/ritonavir), adverse events were reported in 90% of the 50 subjects enrolled. The
most commonly reported adverse events considered related to study treatment were diarrhea (18%) and
vomiting (10%). In the NV20911 study (INVIRASE + ritonavir), 4 subjects (22% of 18 enrolled) experienced
adverse events that were considered related to INVIRASE + ritonavir. These events (n) were vomiting (3),
abdominal pain (1) and diarrhea (1). All reported adverse events were mild or moderate in intensity. The
adverse reaction profile of INVIRASE in the pediatric trials is similar to that observed in adult trials.
6.3
Postmarketing Experience
Additional adverse events identified during postmarketing use are similar to those observed in clinical trials
with INVIRASE and saquinavir soft gel capsules alone or in combination with ritonavir. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to INVIRASE exposure. In addition, torsades de pointes has been
reported rarely [see Warnings and Precautions (5.3)].
7
DRUG INTERACTIONS
Drug interaction studies have been completed with both INVIRASE and saquinavir soft gel capsules.
Observations from drug interaction studies with saquinavir soft gel capsules may not be predictive for
INVIRASE/ritonavir. Because ritonavir is coadministered with INVIRASE, prescribers should also refer to
the prescribing information for ritonavir regarding drug interactions associated with this agent.
9
7.1
Potential for INVIRASE to Affect Other Drugs
The combination INVIRASE/ritonavir is a potent inhibitor of CYP3A and may significantly increase the
exposure of drugs primarily metabolized by CYP3A. Drugs that are contraindicated specifically due to the
observed or expected magnitude of interaction and potential for serious or life-threatening adverse events are
listed in Table 1 [see Contraindications (4)]. Coadministration with other CYP3A substrates may require a
dose adjustment or additional monitoring (see Table 3).
7.2
Potential for Other Drugs to Affect INVIRASE
The metabolism of saquinavir is mediated primarily by CYP3A. Additionally, saquinavir is a substrate for
P-glycoprotein (P-gp). Therefore, drugs that affect CYP3A and/or P-gp may modify the pharmacokinetics of
saquinavir. Coadministration with drugs that are potent inducers of CYP3A (e.g., phenobarbital, phenytoin,
carbamazepine) may result in decreased plasma concentrations of saquinavir and reduced therapeutic effect.
7.3
Established and Other Potentially Significant Drug Interactions
Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers receiving
INVIRASE/ritonavir, additive effects on QT and/or PR interval prolongation may occur with certain members
of the following drug classes: antiarrhythmics class IA or class III, neuroleptics, antidepressive agents, PDE5
inhibitors (when used for pulmonary arterial hypertension), antimicrobials, antihistaminics and others. This
effect might lead to an increased risk of ventricular arrhythmias, notably torsades de pointes. Therefore,
concurrent administration of these agents with INVIRASE/ritonavir is contraindicated [see Contraindications
(4)].
Table 3 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose
or avoidance of the combination may be recommended depending on the interaction.
Table 3
Established and Other Potentially Significant Drug Interactions: Alteration in Dose or
Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted
Interaction with INVIRASE/ritonavir
Concomitant Drug
Effect on
Clinical Comment
Class:
Concentration of
Drug Name
Saquinavir or
Concomitant Drug
HIV-1 Antiviral Agents
Non-nucleoside reverse
transcriptase inhibitor:
b
Delavirdine
↑ Saquinavir
Effect on delavirdine is
not well established
Appropriate doses of the combination with respect to
safety and efficacy have not been established.
Coadministration is not recommended.
Liver function should be monitored frequently if this
combination is prescribed.
Non-nucleoside reverse
transcriptase inhibitor:
a
Efavirenz ,
b
nevirapine
↓ Saquinavir
↔ Efavirenz
Appropriate doses of the combination of efavirenz or
nevirapine and INVIRASE/ritonavir with respect to
safety and efficacy have not been established.
Coadministration is not recommended.
HIV-1 protease
inhibitor:
↑ Saquinavir
↑ Indinavir
Appropriate doses of the combination of indinavir and
INVIRASE/ritonavir with respect to safety and efficacy
have not been established. Coadministration is not
recommended.
Indinavir
b
Increased concentrations of indinavir may result in
10
Concomitant Drug
Class:
Drug Name
HIV-1 protease
inhibitor:
Lopinavir/ritonavira
(coformulated tablet)
Effect on
Concentration of
Saquinavir or
Concomitant Drug
↔ Saquinavir
↔ Lopinavir
↓ Ritonavir
Clinical Comment
nephrolithiasis. For further details see complete
prescribing information for Crixivan® (indinavir).
Evidence from several clinical trials indicates that
saquinavir concentrations achieved with the saquinavir
and lopinavir/ritonavir combination are similar to those
achieved following INVIRASE/ritonavir 1000/100 mg.
The recommended dose for this combination is
INVIRASE 1000 mg plus lopinavir/ritonavir 400/100 mg
bid.
Lopinavir/ritonavir in combination with INVIRASE
should be used with caution. Additive effects on QT
and/or PR interval prolongation may occur with
INVIRASE [see Warnings and Precautions (5.2, 5.3)].
HIV-1 protease
inhibitor:
Nelfinavir
HIV-1 protease
inhibitor:
Tipranavir/ritonavira
↑ Saquinavir
Combining saquinavir/ritonavir with nelfinavir is not
recommended.
↓ Saquinavir
Combining saquinavir with tipranavir/ritonavir is not
recommended.
HIV-1 CCR5
antagonist:
Maraviroc
↑ Maraviroc
Maraviroc dose should be 150 mg twice daily when
coadministered with INVIRASE/ritonavir. For further
details see complete prescribing information for
Selzentry® (maraviroc).
Other Agents
Additive effects on QT and/or PR interval prolongation
may occur with INVIRASE/ritonavir [see
Contraindications (4) and Warnings and Precautions
(5.2, 5.3)]. Coadministration of INVIRASE/ritonavir and
ibutilide or sotalol is not recommended.
Ibutilide
Sotalol
Anticoagulant:
Warfarinb
↑ Warfarin
Concentrations of warfarin may be affected. It is
recommended that INR (international normalized ratio)
be monitored.
Anticonvulsants:
Carbamazepineb,
phenobarbitalb,
phenytoinb
↓ Saquinavir
Saquinavir may be less effective due to decreased
saquinavir plasma concentrations in patients taking these
agents concomitantly. Coadministration is not
recommended.
Anti-gout:
↑ Colchicine
Effect on
carbamazepine,
phenobarbital, and
phenytoin is not well
established
Treatment of gout flares-coadministration of colchicine
11
Concomitant Drug
Class:
Drug Name
Effect on
Concentration of
Saquinavir or
Concomitant Drug
Colchicine
Clinical Comment
in patients on INVIRASE/ritonavir:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half
tablet) 1 hour later. Dose to be repeated no earlier than 3
days.
Treatment of familial Mediterranean fever (FMF)
coadministration of colchicine in patients on
INVIRASE/ritonavir:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg
twice a day).
Prophylaxis of gout-flares-co-administration of
colchicine in patients on INVIRASE/ritonavir:
If the original colchicine regimen was 0.6 mg twice a
day, the regimen should be adjusted to 0.3 mg once a
day.
If the original colchicine regimen was 0.6 mg once a day,
the regimen should be adjusted to 0.3 mg once every
other day.
Patients with renal or hepatic impairment should not be
given colchicine with INVIRASE/ritonavir.
Streptogramin
antibiotics
(quinupristin/dalfopristin
b
)
Fusidic Acid
Streptogramin
antibiotics such as
quinupristin/dalfopristi
n inhibit CYP3A4;
saquinavir
concentrations may be
increased
↑ Saquinavir
↑ Fusidic Acid
↑Ritonavir
Monitoring for saquinavir toxicity is recommended. Use
with caution due to possible cardiac arrhythmias.
Concomitant use of fusidic acid and INVIRASE/ritonavir
is not recommended due to potential for increased mutual
toxicities.
The interaction between INVIRASE/ritonavir and fusidic
acid has not been formally evaluated. Co-administration
of fusidic acid and INVIRASE/ritonavir can cause
increased plasma concentrations of fusidic acid,
saquinavir and ritonavir.
Antifungal:
Ketoconazolea,
itraconazoleb
↔ Saquinavir
↔ Ritonavir
↑ Ketoconazole
When INVIRASE/ritonavir and ketoconazole are
coadministered, plasma concentrations of ketoconazole
are increased (see Table 5). Hence, doses of
ketoconazole or itraconazole >200 mg/day are not
12
Concomitant Drug
Class:
Drug Name
Effect on
Concentration of
Saquinavir or
Concomitant Drug
Clinical Comment
recommended.
Antimycobacterial:
Rifabutina
↔ Saquinavir
↑ Rifabutin
↔ Ritonavir
No dose adjustment of INVIRASE/ritonavir (1000/100
mg bid) is required if INVIRASE/ritonavir is
administered in combination with rifabutin.
Dosage reduction of rifabutin by at least 75% of the
usual dose of 300 mg/day is recommended (i.e., a
maximum dose of 150 mg every other day or three times
per week). Increased monitoring for adverse events
including neutropenia and liver enzyme levels is
warranted in patients receiving the combination.
Consider monitoring rifabutin concentrations to ensure
adequate exposure.
Antipsychotic:
Quetiapine
↑ Quetiapine
Benzodiazepinesb:
↑ Benzodiazepines
Alprazolam, clorazepate,
diazepam, flurazepam
Initiation of INVIRASE with ritonavir in patients taking
quetiapine:
Consider alternative antiretroviral therapy to avoid
increases in quetiapine drug exposures. If
coadministration is necessary, reduce the quetiapine dose
to 1/6 of the current dose and monitor for quetiapineassociated adverse reactions. Refer to the quetiapine
prescribing information for recommendations on adverse
reaction monitoring.
Initiation of quetiapine in patients taking INVIRASE
with ritonavir:
Refer to the quetiapine prescribing information for initial
dosing and titration of quetiapine.
Clinical significance is unknown. Careful monitoring of
patients for benzodiazepine effects is warranted; a
decrease in benzodiazepine dose may be needed.
Benzodiazepineb:
↑ Midazolam
Intravenously
administered Midazolam
Increases in the concentration of midazolam are expected
to be significantly higher with oral than parenteral
administration. Therefore, INVIRASE/ritonavir should
not be given with orally administered midazolam [see
Contraindications (4)]. If INVIRASE/ritonavir is
coadministered with parenteral midazolam, close clinical
monitoring for respiratory depression and/or prolonged
sedation should be exercised and dosage adjustment
should be considered.
Calcium channel
blockersb:
Diltiazem, felodipine,
Caution is warranted and clinical monitoring of patients
is recommended.
↑ Calcium channel
blockers
13
Concomitant Drug
Class:
Drug Name
Effect on
Concentration of
Saquinavir or
Concomitant Drug
Clinical Comment
nifedipine, nicardipine,
nimodipine, verapamil,
amlodipine, nisoldipine,
isradipine
Corticosteroid:
Dexamethasoneb
↓ Saquinavir
INVIRASE/ritonavir may be less effective due to
decreased saquinavir plasma concentrations.
Coadministration is not recommended.
Digitalis Glycosides:
Digoxina
↑ Digoxin
Caution should be exercised when INVIRASE/ritonavir
and digoxin are coadministered; serum digoxin
concentrations should be monitored and the dose of
digoxin may need to be reduced when coadministered
with INVIRASE/ritonavir.
Increases in serum
digoxin concentration
were greater in female
subjects as compared to
male subjects when
digoxin was
coadministered with
INVIRASE/ritonavir.
Endothelin receptor
antagonists:
Bosentan
↑ Bosentan
Coadministration of bosentan in patients on
INVIRASE/ritonavir:
In patients who have been receiving INVIRASE/ritonavir
for at least 10 days, start bosentan at 62.5 mg once daily
or every other day based upon individual tolerability.
Coadministration of INVIRASE/ritonavir in patients on
bosentan:
Discontinue use of bosentan at least 36 hours prior to
initiation of INVIRASE/ritonavir.
After at least 10 days following the initiation of
INVIRASE/ritonavir, resume bosentan at 62.5 mg once
daily or every other day based upon individual
tolerability.
Inhaled beta agonist:
Salmeterol
↑ Salmeterol
Concurrent administration of salmeterol with
INVIRASE/ritonavir is not recommended. The
combination may result in increased risk of
cardiovascular adverse events associated with salmeterol,
including QT prolongation, palpitations and sinus
tachycardia.
Inhaled/nasal steroids:
Fluticasoneb
↑ Fluticasone
Concomitant use of fluticasone propionate and
INVIRASE/ritonavir may increase plasma concentrations
14
Concomitant Drug
Class:
Drug Name
Effect on
Concentration of
Saquinavir or
Concomitant Drug
Budesonide
Clinical Comment
of fluticasone propionate, resulting in significantly
reduced serum cortisol concentrations. Several cases of
Cushing’s disease associated with this interaction have
been reported in the literature. Coadministration of
fluticasone propionate and INVIRASE/ritonavir is not
recommended unless the potential benefit to the patient
outweighs the risk of systemic corticosteroid side effects.
If the combination is nevertheless considered necessary,
a dose reduction of fluticasone propionate with close
monitoring of local and systemic effects is
recommended.
A switch to a corticosteroid which is not a substrate for
CYP3A (e.g., beclomethasone) should be considered. In
case of withdrawal of corticosteroids, progressive dose
reduction may have to be performed over a longer
period.
HMG-CoA reductase
inhibitorsb:
Atorvastatin
↑ Atorvastatin
Titrate atorvastatin dose carefully and use the lowest
dose necessary; do not exceed atorvastatin 20 mg/day.
Patients should be carefully monitored for signs and
symptoms of myopathy (e.g., muscle weakness, muscle
pain, rising creatine kinase).
Immunosuppressantsb: ↑ Immunosuppressants
Cyclosporine, rapamycin
Therapeutic concentration monitoring is recommended
for immunosuppressant agents when coadministered with
INVIRASE/ritonavir.
Narcotic analgesic:
Methadonea
Dosage of methadone may need to be increased when
coadministered with INVIRASE/ritonavir.
↓ Methadone
Use with caution. Additive effects on QT and/or PR
interval prolongation may occur with
INVIRASE/ritonavir [see Contraindications (4) and
Warnings and Precautions (5.2, 5.3)].
Oral contraceptives:
Ethinyl estradiolb
↓ Ethinyl estradiol
Alternative or additional contraceptive measures should
be used when estrogen-based oral contraceptives and
INVIRASE/ritonavir are coadministered.
PDE5 inhibitors
(phosphodiesterase
type 5 inhibitors):
Sildenafila, vardenafilb,
tadalafilb
↑ Sildenafil
↔ Saquinavir
May result in an increase in PDE5 inhibitor-associated
adverse events, including hypotension, syncope, visual
disturbances, and priapism.
↑ Vardenafil
↑ Tadalafil
Use of PDE-5 inhibitors for pulmonary arterial
hypertension (PAH):
Only the combination
15
Concomitant Drug
Class:
Drug Name
Effect on
Concentration of
Saquinavir or
Concomitant Drug
of sildenafil with
saquinavir soft gelatin
capsules has been
studied at doses used
for treatment of erectile
dysfunction.
Clinical Comment
• Use of sildenafil (Revatio) is contraindicated when
used for the treatment of pulmonary arterial
hypertension (PAH) [see Contraindications (4)].
The following dose adjustments are recommended for
use of tadalafil (Adcirca®) with INVIRASE/ritonavir:
Coadministration of Adcirca in patients on
INVIRASE/ritonavir:
In patients receiving INVIRASE/ritonavir for at least one
week, start Adcirca at 20 mg once daily. Increase to 40
mg once daily based upon individual tolerability.
Coadministration of INVIRASE/ritonavir in patients on
Adcirca:
Avoid use of Adcirca during the initiation of
INVIRASE/ritonavir. Stop Adcirca at least 24 hours
prior to starting INVIRASE/ritonavir. After at least one
week following the initiation of INVIRASE/ritonavir,
resume Adcirca at 20 mg once daily. Increase to 40 mg
once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:
Use sildenafil with caution at reduced doses of 25 mg
every 48 hours with increased monitoring of adverse
events when administered concomitantly with
INVIRASE/ritonavir.
Use vardenafil with caution at reduced doses of no more
than 2.5 mg every 72 hours with increased monitoring of
adverse events when administered concomitantly with
INVIRASE/ritonavir.
Use tadalafil with caution at reduced doses of no more
than 10 mg every 72 hours with increased monitoring of
adverse events when administered concomitantly with
INVIRASE/ritonavir.
Tricyclic
antidepressantsb:
Amitriptyline,
clomipramine,
imipramine, maprotiline
↑ Tricyclics
Therapeutic concentration monitoring is recommended
for tricyclic antidepressants when coadministered with
INVIRASE/ritonavir.
16
Concomitant Drug
Class:
Drug Name
Other antidepressants:
Nefazodone
Proton pump
inhibitors:
Omeprazolea
Effect on
Concentration of
Saquinavir or
Concomitant Drug
↑ Saquinavir
Clinical Comment
Monitoring for saquinavir toxicity is recommended.
↑ Saquinavir
When INVIRASE/ritonavir is co-administered with
omeprazole, saquinavir concentrations are increased
significantly. If omeprazole or another proton pump
inhibitor is taken concomitantly with
INVIRASE/ritonavir, caution is advised and monitoring
for potential saquinavir toxicities is recommended,
particularly gastrointestinal symptoms, increased
triglycerides, deep vein thrombosis, and QT
prolongation.
Herbal Products:
St. John’s wortb
(hypericum perforatum)
↓ Saquinavir
Herbal products containing St. John’s wort should not be
used concomitantly with INVIRASE/ritonavir because
coadministration may lead to loss of virologic response
and possible resistance to INVIRASE or to the class of
protease inhibitors.
Other drugs that are
substrates of CYP3A:
Fentanylb
Alfentanilb
Vasodilators
(peripheral):
Intravenously
administered Vincamine
Garlic Capsulesb
↑ Fentanyl
↑Alfentanil
Coadministration with these drugs may accentuate the
side effects reported with use of fentanyl or alfentanil
including respiratory depression, apnea and bradycardia.
↑ Vincamine
Monitoring for vincamine toxicity is recommended. Use
with caution due to potential cardiac arrhythmias.
↓ Saquinavir
Coadministration of garlic capsules and saquinavir is not
recommended due to the potential for garlic capsules to
induce the metabolism of saquinavir which may result in
sub-therapeutic saquinavir concentrations.
a
See Drug Interactions (7), Table 5 and Table 6 for magnitude of interactions.
INVIRASE/ritonavir interaction has not been evaluated.
b
7.4
Drugs without Clinically Significant Interactions with INVIRASE/ritonavir
Based on drug interaction studies conducted with INVIRASE/ritonavir, no clinically significant effect was
observed for saquinavir when coadministered with fosamprenavir. No clinically significant effect was observed
for enfuvirtide when coadministered with INVIRASE/ritonavir.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B
Reproduction studies conducted with saquinavir have shown no embryotoxicity or teratogenicity in both rats
and rabbits. Because of limited bioavailability of saquinavir in animals and/or dosing limitations, the plasma
exposures (AUC values) in the respective species were approximately 29% (using rat) and 21% (using rabbit) of
those obtained in humans at the recommended clinical dose combined with ritonavir. Clinical experience in
17
pregnant women is limited. Saquinavir should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including
INVIRASE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register
patients by calling 1-800-258-4263.
8.3
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed
their infants to avoid risking postnatal transmission of HIV-1.
It is not known whether saquinavir is excreted in human milk. Because of both the potential for HIV-1
transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed
not to breastfeed if they are receiving INVIRASE.
8.4
Pediatric Use
The safety and activity of saquinavir have been evaluated in 68 pediatric subjects 4 months to less than 16 years
of age treated with INVIRASE combined with either ritonavir or with lopinavir/ritonavir in two clinical trials.
Data from the NV20911 trial demonstrated that saquinavir combined with low dose ritonavir provided plasma
levels of saquinavir that were significantly higher than those historically observed in adults at the approved dose
[see Clinical Pharmacology (12.3)]. The HIVNAT 017 trial provided long term 96-week activity and safety
data; however, pharmacokinetic data from this study could not be validated.
HIVNAT 017 was an open-label, single-arm trial at two centers in Thailand that evaluated the use of
INVIRASE (50 mg per kg twice daily given as 200 mg capsules) with lopinavir/ritonavir (230/57.5 mg/m2
twice daily) for 96 weeks. Fifty subjects 4 years to less than 16 years of age were enrolled. In this trial
population, treatment resulted in HIV-1 RNA <400 copies/mL at week 96 in 78% of subjects (HIV-1 RNA <50
copies per mL at week 96 in 66%). Mean CD4 lymphocyte percentage increased from 8% at screening to 22%
at week 96.
NV20911 was an open label, multinational trial that evaluated the pharmacokinetics, safety, and activity of
INVIRASE (50 mg per kg twice daily as 200 mg capsules, up to the adult dose of 1000 mg twice daily) and
ritonavir oral solution plus ≥ 2 background ARVs. Eighteen subjects 4 months to less than 6 years of age were
enrolled. Treatment with INVIRASE/ritonavir resulted in HIV-1 RNA <400 copies per mL at week 48 in 72%
of subjects (HIV-1 RNA <50 copies per mL at week 48 in 61%). The percentage of subjects with HIV-1 RNA
<50 copies per mL at week 48 was 61%. Mean CD4 lymphocyte percentage increased from 29% at screening to
34% at week 48.
Steady state saquinavir exposures observed in pediatric trials were substantially higher than historical data in
adults where dose- and exposure-dependent QTc and PR prolongation were observed [see Warnings and
Precautions (5.3), Clinical Pharmacology (12.2, 12.3)]. Although electrocardiogram abnormalities were not
reported in these pediatric trials, the trials were small and not designed to evaluate QT or PR intervals.
Modeling and simulation assessment of pharmacokinetic/pharmacodynamic relationships in pediatric subjects
suggest that reducing the INVIRASE dose to minimize risk of QT prolongation is likely to reduce antiviral
efficacy. In addition, no clinical efficacy data are available at INVIRASE doses less than 50 mg per kg in
pediatric subjects. Therefore, pediatric dose recommendations that are both reliably effective and below
thresholds of concern with respect to QT and PR prolongation could not be determined.
8.5
Geriatric Use
Clinical trials of INVIRASE did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. In general, dosing INVIRASE in elderly patients
18
should be undertaken with caution keeping in mind the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
8.6
Impaired Renal Function
Renal clearance is a minor elimination pathway; the principal route of excretion for saquinavir is by hepatic
metabolism. Therefore, no initial dose adjustment is necessary for patients with renal impairment. However,
patients with severe renal impairment or end-stage renal disease (ESRD) have not been studied, and caution
should be exercised when prescribing INVIRASE in this population.
8.7
Impaired Hepatic Function
No dosage adjustment is necessary for HIV-1-infected patients with mild or moderate hepatic impairment based
on limited data. In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other
underlying liver abnormalities, there have been reports of worsening liver disease [see Clinical Pharmacology
(12.3)]. INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic
impairment [see Contraindications (4)].
10
OVERDOSAGE
There is limited experience of overdose with saquinavir.
No acute toxicities or sequelae were noted in 1 subject who ingested 8 grams of INVIRASE as a single dose.
The subject was treated with induction of emesis within 2 to 4 hours after ingestion. A second subject ingested
2.4 grams of INVIRASE in combination with 600 mg of ritonavir and experienced pain in the throat that lasted
for 6 hours and then resolved. In an exploratory Phase II study of oral dosing with INVIRASE at 7200 mg per
day (1200 mg q4h), there were no serious toxicities reported through the first 25 weeks of treatment.
Treatment of overdose with saquinavir should consist of general supportive measures including monitoring of
vital signs and ECG and observations of the patient’s clinical status. Since saquinavir is highly protein bound,
dialysis is unlikely to be beneficial in significant removal of the active substance.
11
DESCRIPTION
INVIRASE brand of saquinavir mesylate is an inhibitor of the human immunodeficiency virus type 1 (HIV-1)
protease.
The chemical name for saquinavir mesylate is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide
methanesulfonate
with a molecular formula C38H50N6O5·CH4O3S and a molecular weight of 766.96. The molecular weight of the
free base is 670.86. Saquinavir mesylate has the following structural formula:
Saquinavir mesylate is a white to off-white, very fine powder with an aqueous solubility of 2.22 mg per mL at
25°C.
INVIRASE is available as light brown and green, opaque hard gelatin capsules for oral administration in a 200mg strength (as saquinavir free base). Each capsule also contains the inactive ingredients lactose,
microcrystalline cellulose, povidone K30, sodium starch glycolate, talc, and magnesium stearate. Each capsule
shell contains gelatin and water with the following dye systems: red iron oxide, yellow iron oxide, black iron
oxide, FD&C Blue #2, and titanium dioxide.
19
INVIRASE is also available as a light orange to greyish- or brownish-orange, oval cylindrical, biconvex filmcoated tablet for oral administration in 500-mg strength (as saquinavir free base). Each tablet also contains the
inactive ingredients lactose, microcrystalline cellulose, povidone K30, croscarmellose sodium, and magnesium
stearate. Each film coat contains hypromellose, titanium dioxide, talc, iron oxide yellow, iron oxide red, and
triacetin.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
INVIRASE is an antiviral agent [see Microbiology (12.4)]
12.2
Pharmacodynamics
QTcS interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled
crossover study in 59 healthy adults, with ECG measurements on Day 3. The maximum mean (95% upper
confidence bound) differences in QTcS interval from placebo after baseline-correction were 18.9 (22.0) and
30.2 (33.4) ms for 1000/100 mg twice daily and supratherapeutic 1500/100 mg twice daily of
INVIRASE/ritonavir, respectively. There is a delayed effect between QTc interval change and drug
concentrations, with the maximum placebo-adjusted baseline-corrected QTcS observed at about 12-20 h postdose. INVIRASE/ritonavir 1500/100 mg twice daily resulted in a Day 3 mean Cmax of INVIRASE
approximately 1.4-fold higher than the mean Cmax observed on Day 3 with the approved therapeutic dose in
healthy volunteers (within the same study). QTcS in this study was QT/RR0.319 for males and QT/RR0.337 for
females, which are similar to Fridericia’s correction (QTcF=QT/RR0.3333).
PR and QRS interval prolongations were also noted in subjects receiving INVIRASE/ritonavir in the same
study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval
after baseline-correction were 28.6 (31.6) and 38.4 (41.4) ms for 1000/100 mg twice daily and supratherapeutic
1500/100 mg twice daily saquinavir/ritonavir respectively. The maximum mean (95% upper confidence bound)
difference from placebo in QRS interval after baseline correction were 2.9 (3.9) and 4.4 (5.3) ms for 1000/100
mg twice daily and supratherapeutic 1500/100 mg twice daily INVIRASE/ritonavir respectively. In this study
using healthy subjects, PR interval prolongation of >200 ms was also observed in 40% and 47% of subjects
receiving INVIRASE/ritonavir 1000/100 mg bid and 1500/100 mg bid, respectively, on Day 3. Three (3%) of
subjects in the active control moxifloxacin arm and 5% in the placebo arm experienced PR prolongation of
>200 ms.
12.3
Pharmacokinetics
The pharmacokinetics of INVIRASE/ritonavir 1000/100 mg twice daily have been evaluated in HIV-1-infected
subjects and healthy subjects. Steady-state saquinavir AUC, Cmax, and Cmin in healthy subjects are
approximately 50% higher than observed in HIV-1-infected subjects.
Adults
Absorption and Bioavailability in Adults
Similar bioavailability was demonstrated when INVIRASE 500 mg film-coated tablet (2 x 500 mg) and
INVIRASE 200 mg capsule (5 x 200 mg) were administered with low-dose ritonavir (100 mg) under fed
conditions. The ratio of mean exposures (90% confidence intervals) of tablets vs capsules was 1.10 (1.04-1.16)
for AUC0- and 1.19 (1.14-1.25) for Cmax.
∞
Absolute bioavailability of saquinavir administered as INVIRASE averaged 4% (CV 73%, range: 1% to 9%) in
8 healthy volunteers who received a single 600-mg dose (3 x 200 mg) of saquinavir mesylate following a highfat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). The low bioavailability is thought to be due
to a combination of incomplete absorption and extensive first-pass metabolism.
INVIRASE in combination with ritonavir at a dose of 1000/100 mg twice daily provides saquinavir systemic
exposures over a 24-hour period that are similar to those achieved with saquinavir soft gel capsules with
20
ritonavir 1000/100 mg twice daily and greater than that achieved with saquinavir soft gel capsules 1200 mg
three times daily (see Table 4).
Table 4
Pharmacokinetic Parameters of Saquinavir at Steady-State After Administration of
Different Regimens in HIV-1-Infected Subjects
Dosing Regimen
N
AUCτ
(ng·h/mL)
866 (62)
7249
INVIRASE 600 mg tid (arithmetic mean, %CV)
10
Saquinavir soft gel capsules 1200 mg tid (arithmetic
31
mean)
INVIRASE 1000 mg bid + ritonavir 100 mg bid
24
14607
(geometric mean and 95% CI)
(10218-20882)
Saquinavir soft gel capsules 1000 mg bid + ritonavir
24
19085
100 mg bid (geometric mean and 95% CI)
(13943-26124)
τ is the dosing interval (i.e., 8h if three times daily and 12h if twice daily)
AUC24h
(ng·h/mL)
2598
21747
Cmin
(ng/mL)
79
216
29214
371
(245-561)
433
(301-622)
38170
Food Effect
The mean 24-hour AUC after a single 600-mg oral dose (6 x 100 mg) in healthy volunteers (n=6) was increased
from 24 ng·h/mL (CV 33%), under fasting conditions, to 161 ng·h/mL (CV 35%) when INVIRASE was given
following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). Saquinavir 24-hour AUC
and Cmax (n=6) following the administration of a higher calorie meal (943 kcal, 54 g fat) were on average 2
times higher than after a lower calorie, lower fat meal (355 kcal, 8 g fat). The effect of food has been shown to
persist for up to 2 hours.
INVIRASE/ritonavir should be taken within 2 hours after a meal.
Distribution
The mean steady-state volume of distribution following intravenous administration of a 12-mg dose of
saquinavir (n=8) was 700 L (CV 39%), suggesting saquinavir partitions into tissues. Saquinavir was
approximately 98% bound to plasma proteins over a concentration range of 15 to 700 ng/mL. In 2 subjects
receiving saquinavir mesylate 600 mg three times daily, cerebrospinal fluid concentrations were negligible
when compared to concentrations from matching plasma samples.
Metabolism and Elimination
In vitro studies using human liver microsomes have shown that the metabolism of saquinavir is cytochrome
P450 mediated with the specific isoenzyme, CYP3A4, responsible for more than 90% of the hepatic
metabolism. Based on in vitro studies, saquinavir is rapidly metabolized to a range of mono- and dihydroxylated inactive compounds. In a mass balance study using 600 mg 14C-saquinavir mesylate (n=8), 88%
and 1% of the orally administered radioactivity was recovered in feces and urine, respectively, within 5 days of
dosing. In an additional 4 subjects administered 10.5 mg 14C-saquinavir intravenously, 81% and 3% of the
intravenously administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing.
In mass balance studies, 13% of circulating radioactivity in plasma was attributed to unchanged drug after oral
administration and the remainder attributed to saquinavir metabolites. Following intravenous administration,
66% of circulating radioactivity was attributed to unchanged drug and the remainder attributed to saquinavir
metabolites, suggesting that saquinavir undergoes extensive first-pass metabolism.
Systemic clearance of saquinavir was rapid, 1.14 L/h/kg (CV 12%) after intravenous doses of 6, 36, and 72 mg.
The mean residence time of saquinavir was 7 hours (n=8).
Special Populations
Renal Impairment
21
Saquinavir pharmacokinetics in patients with renal impairment has not been investigated. Only 1% of
saquinavir is excreted in the urine, so the impact of renal impairment on saquinavir elimination would likely be
minimal. However, subjects with severe renal impairment or end-stage renal disease (ESRD) have not been
studied, and concentrations of saquinavir may be elevated in these populations.
Hepatic Impairment
The effect of hepatic impairment on the steady state pharmacokinetics of INVIRASE/ritonavir (1000/100 mg
bid for 14 days) was investigated in 7 HIV-1-infected subjects with moderate liver impairment (6 with ChildPugh score of 7 and 1 with Child-Pugh score of 9). The study included a control group consisting of 7 HIV-1infected subjects with normal hepatic function matched with hepatically impaired subjects for age, gender,
weight and tobacco use. The mean (% coefficient of variation in parentheses) values for INVIRASE AUC0-12
and Cmax were 24.3 (102%) µg·hr/mL and 3.6 (83%) µg/mL, respectively, for HIV-1-infected subjects with
moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) µg·hr/mL and
4.3 (68%) µg/mL. The geometic mean ratio (ratio of pharmacokinetic parameters in hepatically impaired
subjects to subjects with normal liver function) (90% confidence interval) was 0.7 (0.3 to 1.6) for both AUC0-12
and Cmax, which suggests approximately 30% reduction in saquinavir exposure in subjects with moderate
hepatic impairment. No dose adjustment is warranted for INVIRASE in HIV-1-infected patients with mild or
moderate hepatic impairment [see Warnings and Precautions (5.5)].
Gender, Race, and Age
A gender difference was observed, with females showing higher saquinavir exposure than males (mean AUC
56% higher, mean Cmax 26% higher), in the relative bioavailability study comparing INVIRASE 500 mg filmcoated tablets to the INVIRASE 200 mg capsules in combination with ritonavir. There was no evidence that age
and body weight explained the gender difference in this study. A clinically significant difference in safety and
efficacy between men and women has not been reported with the approved dosage regimen (saquinavir 1000mg/ritonavir 100-mg twice daily).
The effect of race on the pharmacokinetics of saquinavir has not been investigated.
The pharmacokinetics of saquinavir have not been evaluated in the elderly.
Pediatric Subjects
Steady-state pharmacokinetic information is available from HIV-1 infected pediatric subjects from study
NV20911. In this study, 5 subjects less than 2 years of age and 13 subjects between 2 and less than 6 years of
age received 50 mg per kg saquinavir twice daily (not to exceed 1000 mg twice daily) combined with ritonavir
at 3 mg/kg for subjects with body weight ranging from 5 to <15 kg or 2.5 mg per kg for subjects with body
weight ranging from 15 to 40 kg (not to exceed 100 mg twice daily). For subjects unable to swallow the
INVIRASE capsules, the contents of INVIRASE 200 mg capsules were mixed with sugar syrup, or sorbitol
syrup (for subjects with Type I diabetes or glucose intolerance), jam, or baby formula. The mean steady state
saquinavir PK parameters for pediatric subjects 2 to less than 6 years of age were: AUC0-12h 37269 ± 18232
ng·h/mL; Ctrough 1811 ± 998 ng/mL; Cmax 5464 ± 2782 ng/mL, and day 3 exposures may be within the range of
exposure associated with QT and PR prolongation [see Clinical Pharmacology: Pharmacodynamics (12.2)].
The subject number was too low and the pharmacokinetic data too variable in the subjects less than 2 years to
establish an appropriate dosing recommendation for this age group. Pharmacokinetic data for subjects ages 6 to
16 years were not available for comparisons with observations from NV20911 [see Use in Specific Populations:
Pediatric Use (8.4)] as the data from HIVNAT 017 could not be validated.
Drug Interactions
Table 5 summarizes the effect of saquinavir soft gel capsules and INVIRASE with and without ritonavir on the
geometric mean AUC and Cmax of coadministered drugs. Table 6 summarizes the effect of coadministered
drugs on the geometric mean AUC and Cmax of saquinavir.
22
Table 5
Effect of Saquinavir (+/- Ritonavir) on the Pharmacokinetics of Coadministered Drugs
Coadministered Drug
Saquinavir soft gel
capsules or saquinavir
soft gel capsules/
ritonavir
N
Dose
% Change for Coadministered Drug
AUC (95% CI)
Cmax (95% CI)
↑45% (17-81%)
↓24% (5-40%)
↑39% (10-76%)
↓34% (14-50%)
Clarithromycin 500 mg bid x 7 days
Clarithromycin
14-OH clarithromycin metabolite
1200 mg tid x 7 days
12V
Sildenafil 100-mg single dose
1200 mg tid x 8 days
27V
↑210% (150-300%)
↑140% (80-230%)
Efavirenz 600 mg qd
1200 mg tid
13V
↓12%
↓13%
INVIRASE/ritonavir
Dose
Digoxin 0.5 mg single dose
1000/100 mg bid x 16 days 16V
↑49% (32-69%)^
↑27% (5-54%)^
R-Methadone 60-120 mg qd
1000/100 mg bid x 14 days 12M
↓19% (9-29%)^
NA
Ketoconazole 200 mg/day
1000/100 mg bid
12V
↑168% (146-193%)^
↑45% (32-59%)^
Midazolam 7.5 mg oral single dose
1000/100 mg bid
16V ↑1144% (975-1339%)^
Rifabutin 150 mg q4d
1000/100 mg bid
11V
↑
↓
↔
*
^
†
§
S
V
M
NA
↑60%†*
(43-79%)^
§
↔ (-10 to 13%)^
↑327% (264 -402%)^
↑111%†*
(75-153%)^
↑68%§ (38-105%)^
Denotes an average increase in exposure by the percentage indicated.
Denotes an average decrease in exposure by the percentage indicated.
Denotes no statistically significant change in exposure was observed.
Compared to rifabutin 150 mg QD
90% Confidence Interval
AUC0-96hr and Cmax of the active moiety (rifabutin + 25-O-desacetyl rifabutin)
AUC0-96hr and Cmax for rifabutin only
Subjects
Healthy Volunteers
Methadone-dependent, HIV negative subjects. None of the 12 subjects experienced withdrawal symptoms.
Not Available
23
Table 6
Effect of Coadministered Drugs on Saquinavir Pharmacokinetics
Coadministered Drug
Saquinavir soft gel
capsules or
saquinavir soft gel
capsules/ritonavir
N
Dose
% Change for Saquinavir
AUC (95% CI)
Cmax (95% CI)
Clarithromycin 500 mg 1200 mg tid x 7 days
bid x 7 days
12V
↑177% (108-269%)
↑187% (105-300%)
Efavirenz 600 mg qd
13V
↓62%
↓50%
Indinavir 800 mg q8h x 1200 mg single dose
2 days
6V
↑364% (190-644%)
↑299% (138-568%)
Ritonavir 400 mg bid x 400 mg bid x 14
14 days
days†
8V
↑121% (7-359%)
↑64%§
1200 mg tid
Lopinavir/ritonavir
Evidence from several clinical trials indicates that saquinavir concentrations achieved with saquinavir
1000 mg + lopinavir/ritonavir 400/100 mg BID are similar to those achieved following
saquinavir/ritonavir 1000/100 mg BID.
Coadministered Drug
INVIRASE or
INVIRASE/ritonavir
N
Dose
% Change for Saquinavir
AUC (95% CI)
Cmax (95% CI)
Atazanavir 300 mg qd 1600/100 mg qd
18S
↑60%
(16-122%)
↑42%
(10-84%)
Ritonavir 100 mg bid
1000 mg bid‡
24S
↑1124%
↑1325%
Tenofovir 300 mg qd
1000 mg bid/100 mg
bid
18S
↔
↔
Tipranavir 500 mg +
ritonavir 200 mg bid
600 mg bid/100 mg
bid
20S
↓76%
(68-81%)^
↓70%
(60-77%)^
Omeprazole 40 mg
qd x 5 days
1000/100 mg bid x 15
days
19V
↑82%
(37-234%)^
↑ 75%
(31-234%)^
Ketoconazole 200
mg/day
1000 mg bid/100 mg
bid
20V
↔^
↔
Rifabutin 150 mg q3d
1000 mg bid/100 mg
bid
19V
↓13%
(-31% to 9%)^
↓15%
(-32% to 7%)^
↑
↓
↔
†
‡
§
^
S
V
Denotes an average increase in exposure by the percentage indicated.
Denotes an average decrease in exposure by the percentage indicated.
Mean change <10%
Compared to saquinavir soft gel capsules 1200 mg tid regimen (n=33).
Compared to INVIRASE 600 mg tid regimen (n=114).
Did not reach statistical significance.
90% Confidence Interval
Subjects
Healthy Volunteers
The HIV-1 antiviral drugs didanosine, tenofovir, and zidovudine are not predicted to have any clinically
significant effect on the pharmacokinetics of saquinavir with and without ritonavir. No clinically significant
effect on the pharmacokinetic parameters of enfuvirtide was observed with coadministration of
INVIRASE/ritonavir. No clinically significant effect on the pharmacokinetic parameters of saquinavir was
observed with coadministration of fosamprenavir.
24
12.4
Microbiology
Mechanism of Action
Saquinavir is an inhibitor of HIV-1 protease. HIV-1 protease is an enzyme required for the proteolytic cleavage
of viral polyprotein precursors into individual functional proteins found in HIV-1 particles. Saquinavir is a
peptide-like substrate analogue that binds to the protease active site and inhibits the activity of the enzyme.
Saquinavir inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature
noninfectious viral particles.
Antiviral Activity
The antiviral activity of saquinavir was assessed in lymphoblastoid and monocytic cell lines and in peripheral
blood lymphocytes in cell culture. Saquinavir inhibited HIV-1 activity in both acutely and chronically infected
cells. EC50 and EC90 values (50% and 90% inhibitory concentrations) ranged from 1 to 30 nM and 5 to 80 nM,
respectively. In the presence of 40% human serum, the mean EC50 of saquinavir against laboratory strain HIV-1
RF in MT4 cells was 37.7± 5 nM representing a 4-fold increase in the EC50 value. In cell culture, saquinavir
demonstrated additive to synergistic effects against HIV-1 in combination with reverse transcriptase inhibitors
(didanosine, lamivudine, nevirapine, stavudine and zidovudine) without enhanced cytotoxicity. Saquinavir in
combination with the protease inhibitors amprenavir, atazanavir, or lopinavir resulted in synergistic antiviral
activity. Saquinavir displayed antiviral activity in cell culture against HIV-1 clades A-H (EC50 values ranged
from 0.9 to 2.5 nM). The EC50 and EC90 values of saquinavir against HIV-2 isolates in cell culture ranged from
0.25 nM to 14.6 nM and 4.65 nM to 28.6 nM, respectively.
Resistance
HIV-1 isolates with reduced susceptibility to saquinavir have been selected during passage in cell culture.
Genotypic analyses of these isolates showed several amino acid substitutions in the HIV-1 protease. Only the
G48V and L90M substitutions were associated with reduced susceptibility to saquinavir, and conferred an
increase in the EC50 value of 8- and 3-fold, respectively.
HIV-1 isolates with reduced susceptibility (≥4-fold increase in the EC50 value) to saquinavir emerged in some
subjects treated with INVIRASE. Genotypic analysis of these isolates identified resistance conferring primary
amino acid substitutions in the protease G48V and L90M, and secondary substitutions L10I/R/V, I54V/L,
A71V/T, G73S, V77I, V82A and I84V that contributed additional resistance to saquinavir. Forty-one isolates
from 37 subjects failing therapy with INVIRASE had a median decrease in susceptibility to saquinavir of 4.3fold.
The degree of reduction in cell culture susceptibility to saquinavir of clinical isolates bearing substitutions
G48V and L90M depends on the number of secondary substitutions present. In general, higher levels of
resistance are associated with greater number of substitutions only in association with either or both of the
primary substitutions G48V and L90M. No data are currently available to address the development of
resistance in patients receiving saquinavir/ritonavir.
Cross-resistance
Among protease inhibitors, variable cross-resistance has been observed. In one clinical study, 22 HIV-1 isolates
with reduced susceptibility (>4-fold increase in the EC50 value) to saquinavir following therapy with
INVIRASE were evaluated for cross-resistance to amprenavir, indinavir, nelfinavir and ritonavir. Six of the 22
isolates (27%) remained susceptible to all 4 protease inhibitors, 12 of the 22 isolates (55%) retained
susceptibility to at least one of the protease inhibitors and 4 out of the 22 isolates (18%) displayed broad crossresistance to all protease inhibitors. Sixteen (73%) and 11 (50%) of the 22 isolates remained susceptible (<4fold) to amprenavir and indinavir, respectively. Four of 16 (25%) and nine of 21 (43%) with available data
remained susceptible to nelfinavir and ritonavir, respectively.
25
After treatment failure with amprenavir, cross-resistance to saquinavir was evaluated. HIV-1 isolates from
22/22 subjects failing treatment with amprenavir and containing one or more substitutions M46L/I, I50V, I54L,
V32I, I47V, and I84V were susceptible to saquinavir.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies found no indication of carcinogenic activity in rats and mice administered saquinavir
for approximately 2 years. Because of limited bioavailability of saquinavir in animals, the plasma exposures
(AUC values) in the respective species were approximately 29% (using rat) and 65% (using mouse) of those
obtained in humans at the recommended clinical dose combined with ritonavir.
Mutagenesis
Mutagenicity and genotoxicity studies, with and without metabolic activation where appropriate, have shown
that saquinavir has no mutagenic activity in vitro in either bacterial (Ames test) or mammalian cells (Chinese
hamster lung V79/HPRT test). Saquinavir does not induce chromosomal damage in vivo in the mouse
micronucleus assay or in vitro in human peripheral blood lymphocytes, and does not induce primary DNA
damage in vitro in the unscheduled DNA synthesis test.
Impairment of Fertility
No adverse effects were reported in fertility and reproductive performance study conducted in rats. Because of
limited bioavailability of saquinavir in animals, the maximal plasma exposures achieved in rats were
approximately 26% of those obtained in humans at the recommended clinical dose combined with ritonavir.
14
CLINICAL STUDIES
14.1
Description of Clinical Studies in Adults
In a randomized, double-blind clinical study NV14256 in zidovudine-experienced, HIV-1-infected adult
subjects, INVIRASE in combination with zalcitabine2 was shown to be superior to either INVIRASE or
zalcitabine monotherapy in decreasing the cumulative incidence of clinical disease progression to AIDSdefining events or death. In another randomized study ACTG229/NV14255, subjects with advanced HIV-1
infection with history of prolonged zidovudine treatment were administered INVIRASE 600 mg (three times
daily) + zidovudine + zalcitabine. Subjects receiving this regimen experienced greater increases in CD4+ cell
counts as compared to those who received INVIRASE + zidovudine or zalcitabine + zidovudine. It should be
noted the HIV treatment regimens that were used in these clinical trials are no longer considered standard of
care.
In the MaxCmin1 trial, saquinavir gel capsule 1000 mg twice daily coadministered with ritonavir 100 mg twice
daily was evaluated in a heterogeneous population of 148 HIV-1-infected subjects. A total of 42 subjects
enrolled were treatment naïve, and 106 subjects were treatment experienced (of which 52 subjects had HIV-1
RNA < 400 copies/mL at baseline). Results showed that 91/148 (61%) subjects achieved and/or sustained an
HIV-1 RNA <400 copies per mL at the completion of 48 weeks treatment.
16
HOW SUPPLIED/STORAGE AND HANDLING
INVIRASE 200-mg capsules are light brown and green opaque capsules with ROCHE and 0245 imprinted on
the capsule shell—bottles of 270 (NDC 0004-0245-15).
INVIRASE 500-mg film-coated tablets are light orange to greyish- or brownish-orange, oval cylindrical,
biconvex tablets with ROCHE and SQV 500 imprinted on the tablet face—bottles of 120 (NDC 0004-0244-51).
2
No longer available in the US.
26
The capsules and tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature] in tightly closed bottles.
17
PATIENT COUNSELING INFORMATION
• Advise the patient to read the FDA-approved patient labeling (Medication Guide).
A statement to patients and health care providers is included on the product’s bottle label: ALERT: Find out
about medicines that should NOT be taken with INVIRASE.
INVIRASE is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with
HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when
using INVIRASE.
Advise patients to avoid doing things that can spread HIV-1 infection to others.
•
•
•
•
Do not share needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor
blades.
Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane
condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Do not breastfeed. We do not know if INVIRASE can be passed to your baby in your breast milk and
whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be
passed to the baby in the breast milk.
Pregnancy
An Antiretroviral Pregnancy Registry has been established. See Pregnancy (8.1) for information on how to
enroll.
Drug Interactions
INVIRASE may interact with some drugs; therefore, advise patients to report to their doctor the use of any
other prescription, nonprescription medication, or herbal products, particularly St. John’s wort.
PR and QT Interval Prolongation
Inform patients that INVIRASE may produce changes in the electrocardiogram (PR interval or QT interval
prolongation). Patients should consult their health care provider if they are experiencing symptoms such as
dizziness, lightheadedness, or palpitations.
Fat Redistribution
Inform patients that redistribution or accumulation of body fat may occur in patients receiving protease
inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
Dosing Instructions
Advise patients that INVIRASE must be used in combination with ritonavir, which significantly inhibits
saquinavir’s metabolism to provide increased plasma saquinavir levels.
Advise patients that INVIRASE administered with ritonavir should be taken within 2 hours after a full meal
[see Clinical Pharmacology (12.3)]. When INVIRASE is taken without food, concentrations of saquinavir in
the blood are substantially reduced and may result in no antiviral activity. Advise patients of the importance of
taking their medication every day, as prescribed, to achieve maximum benefit. Patients should not alter the dose
or discontinue therapy without consulting their physician. If a dose is missed, patients should take the next dose
as soon as possible. However, the patient should not double the next dose.
27
28
Medication Guide
INVIRASE (in-ver-ase)
(saquinavir mesylate)
capsules
®
INVIRASE (in-ver-ase)
(saquinavir mesylate)
tablets
®
Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with INVIRASE.
For more information, see the section “Who should not take INVIRASE?”
Read this Medication Guide before you start taking INVIRASE and each time you get a refill. There may be new
information. This Medication Guide does not take the place of talking to your healthcare provider about your medical
condition or treatment. You and your healthcare provider should talk about your treatment with INVIRASE before you start
taking it and at regular checkups. You should stay under a healthcare provider’s care when taking INVIRASE.
Also read the Medication Guide for ritonavir (NORVIR).
What is the most important information I should know about INVIRASE?
• INVIRASE must be taken along with ritonavir (NORVIR).
®
• INVIRASE should not be taken along with cobicistat (TYBOST ).
INVIRASE may cause serious side effects including:
• Interactions with other medicines. It is important to know the medicines that should not be taken with INVIRASE.
Read the section “What should I tell my healthcare provider before taking INVIRASE?”
• Changes in your heart rhythm and the electrical activity of your heart. These changes may be seen on an EKG
(electrocardiogram) and can lead to serious heart problems. Your risk for these problems may be higher if you:
• already have a history of abnormal heart rhythm, including Congenital Long QT Syndrome, or other types of heart
disease.
• take other medicines that can affect your heart rhythm while you take INVIRASE.
Tell your healthcare provider right away if you have any of these symptoms while taking INVIRASE:
• dizziness
• fainting
• lightheadedness
• sensation of abnormal heartbeats
See the section below “What are the possible side effects of INVIRASE?” for more information about serious
side effects.
What is INVIRASE?
INVIRASE is a prescription HIV-1 (Human Immunodeficiency Virus) medicine used with ritonavir and other antiretroviral
medicines to treat HIV-1 in people over 16 years of age.
HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).
In children, INVIRASE doses that are both effective and safe could not be determined.
When used with other antiretroviral medicines to treat HIV-1, INVIRASE may help:
• reduce the amount of HIV-1 in your blood.
• increase the number of white blood cells called CD4+ (T) cells in your blood which help fight off other infections.
Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system.
This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic
infections.)
INVIRASE does not cure HIV infection or AIDS. You must stay on continuous HIV therapy to control HIV infection and
decrease HIV-related illnesses.
Avoid doing things that can spread HIV-1 infection to others:
•
•
•
Do not share or re-use needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to
lower the chance of sexual contact with semen, vaginal secretions, or blood.
Ask your healthcare provider if you have any questions about how to prevent passing HIV-1 to other people.
Who should not take INVIRASE?
Do not take INVIRASE if you have the following conditions:
• a condition called Congenital Long QT Syndrome.
• complete AV (atrioventricular) heart block and you do not have a pacemaker or you are at risk for complete AV heart
block.
• low potassium or low magnesium in your blood.
• severe liver problems.
29
•
you have had a severe allergic reaction to saquinavir mesylate or any of the ingredients in INVIRASE. See the end of
this Medication Guide for a complete list of ingredients in INVIRASE.
Talk to your healthcare provider before taking INVIRASE if you have any of the conditions listed above.
Taking INVIRASE with certain other medicines can cause serious problems or life threatening reactions.
Do not take INVIRASE with ritonavir (NORVIR) if you take any of the following medicines:
• alfuzosin (Uroxatral )
®
®
• amiodarone (Cordarone , Pacerone )
®
• atazanavir (Revataz )
• bepridil
• cisapride
®
• clarithromycin (Biaxin )
®
• clozapine (Clozaril )
• dapsone
®
• dofetilide (Tikosyn )
®
• disopyramide (Norpace )
• Ergot containing medicines, including:
• dihydroergotamine mesylate (D.H.E. 45, Embolex, Migranal )
• ergonovine, ergonovine and methylergonovine (Ergotrate, Methergine), ergotamine and methylergonovine
• ergotamine tartrate (Cafergot, Migergot, Ergomar, Ergostate Medihaler Ergotamine, Wigraine Wigrettes)
• erythromycin
®
• flecainide (Tambocor )
• halofantrine
®
• haloperidol (Haldol )
• lidocaine
®
®
®
• lovastatin (Advicor , Altoprev , Mevacor )
• midazolam hydrochloride oral syrup
®
®
• pentamidine (Nebupent , Pentam 300)
• Phenothiazine containing medicines, including:
o chlorpromazine
o mesoridazine
o thioridazine
®
• pimozide (Orap )
®
• propafenone (Rhythmol )
• quinidine
®
• quinine (Qualaquin )
®
®
®
®
• rifampin (Rifadin , Rifamate , Rifater , Rimactane )
®
• sildenafil (Revatio )
®
®
®
• simvastatin (Simcor , Vytorin , Zocor )
®
• tacrolimus (Prograf )
®
• trazodone (Oleptro )
®
• triazolam (Halcion )
• ziprasidone
Talk to your healthcare provider before taking INVIRASE if you take any of the medicines listed above.
®
What should I tell my healthcare provider before taking INVIRASE?
Before taking INVIRASE, tell your healthcare provider about all of your medical conditions, including if you:
• have any heart problems, including a condition called Congenital Long QT Syndrome.
• have diabetes.
• have liver problems, including Hepatitis B or Hepatitis C.
• have hemophilia. People who take INVIRASE may have increased bleeding.
• are pregnant or plan to become pregnant. It is not known if INVIRASE will harm your unborn baby.
Pregnancy Registry: There is a pregnancy registry for women who take antiretroviral medicines during pregnancy.
The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare
provider about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. You should not breastfeed if you have HIV because of the risk of passing HIV
30
to your baby. Do not breastfeed if you take INVIRASE. We do not know if INVIRASE can be passed to your baby in
your breast milk and whether it could harm your baby. Talk to your healthcare provider about the best way to feed
your baby.
Tell your healthcare provider about all the medicines you take, including prescriptions and over-the-counter
medicines, vitamins and herbal supplements. Tell your healthcare provider if you take St. John’s wort.
INVIRASE may affect the way other medicines work, and other medicines may affect how INVIRASE works. Do not start
taking a new medicine without talking with your healthcare provider or pharmacist. Your healthcare provider can tell you if
it is safe to take INVIRASE with other medicines.
How should I take INVIRASE?
• Take INVIRASE exactly as your healthcare provider tells you.
• INVIRASE comes as a 500 mg tablet or a 200 mg capsule.
• Do not change your dose of INVIRASE or stop treatment without first talking with your healthcare provider. Stay under
the care of your healthcare provider during treatment with INVIRASE.
• INVIRASE must be used along with ritonavir (NORVIR).
• Take INVIRASE up to 2 hours after a meal.
• Do not miss a dose of INVIRASE. It is very important to take your medicine every day. If you skip doses or take less
than the prescribed dose the medicine will not work as well, and the virus may become harder to treat.
• If you miss a dose of INVIRASE, you should take the next dose as soon as possible. Do not double your dose.
• If you take too much INVIRASE, call your healthcare provider or go to the nearest hospital emergency room right
away.
• If you are unable to swallow INVIRASE capsules whole, you may open the capsule and mix the contents with sugar
syrup or jam. People with type 1 diabetes or glucose intolerance should use sorbitol syrup.
o Use a medicine cup to measure 15 mL of the syrup or jam into a container. You can ask your pharmacist for a
medicine cup if you do not have one.
o Open the capsule and pour the contents into the container with the syrup or jam.
o Mix with a spoon for 30 to 60 seconds.
o Let the mixture come to room temperature.
o Eat the entire mixture. Be sure to take the full dose.
What are the possible side effects of INVIRASE?
INVIRASE can cause serious side effects.
• See “What is the most important information I should know about INVIRASE?”
• Diabetes and high blood sugar. Some people who take protease inhibitors including INVIRASE get new or more
serious diabetes, or high blood sugar. Tell your healthcare provider if you notice an increase in thirst or urinate more
often than normal while taking INVIRASE.
• Liver problems. People with liver problems such as Hepatitis B or C, cirrhosis or have a history of alcoholism may
have worsening liver problems. Tell your healthcare provider right away if you have any of these signs and symptoms
of liver problems:
o loss of appetite
o pale colored stools
o yellowing of your skin or whites of your eyes
o itchy skin
(jaundice)
o stomach area (abdominal) pain
o dark-colored urine
•
•
•
•
Increased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with
protease inhibitors including INVIRASE.
Increase in certain fat (cholesterol and triglycerides) levels in your blood. Your healthcare provider will check
your blood for high levels of cholesterol and triglycerides before you start INVIRASE and during treatment with
INVIRASE.
Changes in body fat can happen in people who take HIV medicine. These changes may include increased amount
of fat in the upper back and neck (“buffalo hump”), breasts, and around the middle of your body (trunk). Loss of fat
from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are
not known.
Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV
medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for
a long time. Tell your healthcare provider if you start having new or worse symptoms of infection after starting your
HIV medicine.
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Common side effects of INVIRASE include:
• nausea
• tiredness
• vomiting
• pneumonia
• diarrhea
• changes in body fat
• stomach area (abdominal) pain
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of INVIRASE. For more information, ask your healthcare provider or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Genentech at 1-800-835-2555.
How should I store INVIRASE?
• Store INVIRASE at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep INVIRASE in a tightly closed container.
Keep INVIRASE and all medicine out of the reach of children.
General information about INVIRASE.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use INVIRASE
for a condition for which it was not prescribed. Do not give INVIRASE to other people even if they have the same
condition you have. It may harm them.
This Medication Guide summarizes the most important information about INVIRASE. If you would like more information,
talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about INVIRASE
that is written for health professionals.
For more information, go to http://www.gene.com/gene/products/information/invirase or call 1-877-436-3683.
What are the ingredients in INVIRASE?
Active ingredient: saquinavir mesylate
Inactive ingredients:
200 mg Capsule: lactose, microcrystalline cellulose, povidone K30, sodium starch glycolate, talc, and magnesium
stearate. Capsule shell: gelatin and water with the following dye systems: red iron oxide, yellow iron oxide, black iron
oxide, FD&C Blue #2, and titanium dioxide.
500 mg Tablet: lactose, microcrystalline cellulose, povidone K30, croscarmellose sodium, and magnesium stearate.
Film coat: hypromellose, titanium dioxide, talc, iron oxide yellow, iron oxide red, and triacetin.
The brands listed are trademarks of their respective owners and are not trademarks of Roche Laboratories, Inc. The makers of these brands are not affiliated with and do not
endorse Roche Laboratories, Inc. or its products.
INVIRASE is a registered trademark of Hoffmann-La Roche Inc.
Capsules Manufactured by: Roche Farma, S.A., Leganes, Spain
Tablets Manufactured by: Roche Farma, S.A., Leganes, Spain
© 2015 Genentech, Inc. All rights reserved.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: December 2015
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